1. Field of the Invention
This invention in the field of molecular biology and medicine is directed to knockout mice in which the mig-6 gene is disrupted resulting in animals which develop early-onset joint abnormalities characteristic of osteoarthritis and are highly susceptible to tumorigenesis of a number of types of cancer, primarily lung cancer. These animals serve as models for testing potential drugs and other therapeutic measures to prevent or treat osteoarthritis, and to delay or attenuate tumor development and growth in humans.
2. Description of the Background Art
Degenerative joint disease, or osteoarthritis affects nearly 12% of the United States population between the ages of 25 and 74 (Lawrence, R C et al. J. Rheumatol. 16:427-41, 1989), and greatly interferes with quality of life by causing acute and chronic pain and disability. The characteristic features of this disease are joint pain, stiffness, joint enlargement and mal-alignment, damage of articular cartilage, and formation of osteophytes or bony outgrowths at the margin of synovial and cartilage junction. Currently, therapy is directed towards controlling symptoms and no disease modifying, or chondroprotective treatment is available. In addition, the costs for pain relief medication are astronomical. Although several genetic and biomechanical factors including heredity, obesity, injury and joint overuse are thought to contribute to the development of osteoarthritis, the molecular mechanism underlying this disease is still elusive. For a comprehensive discussion of osteoarthritis, see, for example, Koopman, W. J., In: Arthritis and Allied Conditions, A Textbook of Rheumatology, 13th Edition, Vol. 2 (Williams & Wilkins, Baltimore, Md., 1997; Redneck, D., Diagnosis of Bone and Joint Disorders, 4th Ed, Vol. 2 (WB Saunders Company, Philadelphia, Pa., 2002). Prior to the present invention, there was no known association between the Mig-6 gene and osteoarthritis.
Mig-6, also known as gene 33 or RALT (Florentine et al., Mol. Cell. Biol. 20:7735-50, 2000; Making et al., J. Biol. Chem. 275:17838-47, 2000), has been mapped to human chromosome 1p36. Mig-6 is an immediate early response gene that can be induced by stressful stimuli and growth factors, as well as by the oncoprotein Ras (Florentine et al., supra; Making et al., supra; Tsoumada et al., Cancer Res. 62, 5668-71, 2002). Mig-6 protein can directly interact with all four members of the ErbB family, including EGFR and ErbB2-4, and it acts as a negative feedback regulator of the ErbB receptor tyrosine kinase (RTK) pathway (Florentine et al., supra; Anastasia et al., Oncogene 22:4221-34, 2003; XII et al., J. Biol. Chem. 280:2924-33, 2005). Recently, it has been reported that down-regulated expression of the Mig-6 gene is observed in human breast carcinomas, which correlates with reduced overall survival of breast cancer patients (Matched et al., Cancer Res. 64:844-56, 2004; Anastasi et al., 2005). However, no mutations in Mig-6 have been detected in human breast carcinomas (Anastasi et al., Oncogene 24:4540-48, 2005). Indeed, no mutations have been reported in Mig-6 to date, and the role of Mig-6 in human lung, gallbladder, and bile duct carcinogenesis has not been assessed.
Allelic loss of chromosome 1p36 is among the most prominent genetic abnormalities observed in human lung cancer (Fujii et al., Cancer Res. 62:3340-46, 2002; Girard et al., Cancer Res. 60:4894-4906, 2000; Nomoto et al., Cancer 28:342-46, 2000), indicating that a critical tumor suppressor gene(s) exists in this locus. Moreover, loss of heterozygosity (LOH) of the distal region of mouse chromosome 4, a region syntenic with human chromosome 1p36, is also frequently observed in mouse lung carcinogenesis (Herzog et al., Oncogene 11:1811-15 1995; Herzog et al., Cancer Res. 62:6424-29, 2002). The p53 tumor suppressor gene homologue, p73, is located in 1p36, but no mutations have been identified in human lung cancers (Nomoto et al., Cancer Res. 58:1380-83, 1998), excluding it as the responsible tumor suppressor gene.